Lactate regulates pathological cardiac hypertrophy via histone lactylation modification

Prolonged pressure overload stimulates the activation of embryonic genes, leading to myocardial hypertrophy and ventricular remodeling, which can eventually progress to heart failure. Identifying effective therapeutic targets is essential for preventing and treating myocardial hypertrophy. Histone lysine lactylation (HKla) is a newly discovered post-translational modification that links cellular metabolism to epigenetic regulation. However, the role of HKla in pathological cardiac hypertrophy remains poorly understood.

Our study explores whether HKla contributes to the development of cardiac hypertrophy. We observed elevated HKla expression in cardiomyocytes from a cardiac hypertrophy animal model induced by transverse aortic constriction and in neonatal mouse cardiomyocytes treated with angiotensin II (Ang II). Further research shows that HKla levels are regulated by glucose metabolism and lactate production, exhibiting dynamic responses to environmental stimuli. In vitro experiments reveal that both exogenous lactate and glucose increase HKla expression and promote cardiac hypertrophy. In contrast, blocking lactate production with inhibitors—such as 2-deoxy-D-glucose (2-DG), oxamate (an LDH inhibitor), and GNE-140 (an LDHA inhibitor)—reduces HKla levels and suppresses hypertrophic development.

Together, these findings highlight the critical role of H3K18la in pathological cardiac hypertrophy and suggest it as a promising therapeutic target for this condition.